Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from expansion (>37 units) of a polyglutamine tract in huntingtin, a 350 kDa protein of unknown function (1). The N-terminal region of huntingtin contains the glutamine repeat, which is encoded by exon1 of the HD gene. Normal huntingtin is a cytoplasmic protein and is expressed ubiquitously, but N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and form aggregates. A large body of evidence has shown that N-terminal huntingtin with expanded glutamine repeats is toxic and can kill cells (2–8). For example, transgenic mice (R6/2) expressing the HD exon1 protein with more than 115 glutamines develop neurological symptoms and neuronal intranuclear inclusions consisting of huntingtin aggregates (2). Similar nuclear aggregates are found in patients with HD (3–5) and other polyglutamine diseases (9).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
HD Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72, 971–983.
Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A. H., Ross, C. A., et al. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548.
DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., and Aronin, N. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dys-trophic neurites in brain. Science 277, 1990–1993.
Becher, M. W., Kotzuk, J. A., Pavlakis, G. N., Sharp, A. H., Davies, S. W., Bates, G. P., et al. (1998) Intranuclear neuronal inclusions in Huntington’s disease and Dentatorubral and Pallidoluysian Arophy: Correlation between the density of inlcusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4, 387–397.
Gutekunst, C.A., Li, S. H., Yi, H., Mulroy, J. S., Kuemmerle, S., Jones, R., et al. (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534.
Saudou, F., Finkbeiner, S., Devys, D. and Greenberg, M. E. (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66.
Peters, M. F., Nucifora, F. C., Jr., Kushi, J., Seaman, H. C., Cooper, J. K., Herring, W. J., et al. (1999) Nuclear targeting of mutant Huntingtin increases toxicity. Mol. Cell. Neurosci. 14, 121–128.
Lunkes, A. and Mandel, J. L. (1998) A cellular model that recapitulates major pathogenic steps of Huntington’s disease. Hum. Mol. Genet. 7, 1355–1361.
Perutz, M.F., Johnson, T., Suzuki, M. and Finch, J.T. (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 91, 5355–5358.
Li, S. H. and Li, X. J. (1998) Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats. Hum. Mol. Genet. 7, 777–782.
Lah, J. J. and Burry, R. W. (1993) Neuronotypic differentiation results in reduced levels and altered distribution of synaptophysin in PC12 cells. J. Neurochem. 60, 503–512.
Li, S.-H., Lam. S., Cheng, A. L., and Li, X.-J. Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum. Mol. Genet. 9, 2859–2867.
Li, S. H., Cheng, A. L., Li, H., and Li, X. J. (1999) Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J. Neurosci. 19, 5159–5172.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Humana Press Inc.
About this protocol
Cite this protocol
Li, SH., Li, XJ. (2003). In Vitro Expression Systems for the Huntington Protein. In: Potter, N.T. (eds) Neurogenetics. Methods in Molecular Biology™, vol 217. Springer, Totowa, NJ. https://doi.org/10.1385/1-59259-330-5:277
Download citation
DOI: https://doi.org/10.1385/1-59259-330-5:277
Publisher Name: Springer, Totowa, NJ
Print ISBN: 978-0-89603-990-2
Online ISBN: 978-1-59259-330-9
eBook Packages: Springer Protocols